The present invention relates generally to the field of ophthalmology. In particular, the invention relates to the treatment of glaucoma using a combination of a glutamate antagonist to preserve visual field and an intraocular pressure lowering compound.
Although the underlying causes of glaucoma are not well understood at this time, glaucoma is characterized by damage to the optic nerve, accompanied by a decrease in the normal visual field. One early warning sign of possible glaucomatous visual field loss is elevated intraocular pressure (xe2x80x9cIOPxe2x80x9d). In fact, glaucoma has historically been treated by medically and /or surgically lowering elevated IOP, for example, by the administration of IOP-lowering agents such as miotics, xcex1 and xcex1/xcex2 adrenergic agonists, beta-blockers, and carbonic anhydrase inhibitors. However, factors other than IOP may play a role in the occurrence of visual field loss. Degeneration of retinal ganglion cells may be related to ischemia or mechanical distortion of the nerve fibers as they exit through the optic nerve head or from pathological perturbations of the retina.
There has been a growing interest in retinal dysfunction as a contributor to the glaucomatous process. Retinal dysfunction, and hence pathology, may be related to ischemia or excitotoxicity. Excitotoxicity is neuronal injury due to excessive excitatory amino acid (xe2x80x9cEAAxe2x80x9d) stimulation. In the inner retina, glutamate is the major EAA that permits the bipolar and amacrine cells to communicate with the ganglion cell. In the central nervous system, excitotoxicity results from hypoxia, ischemia, hypoglycemia or trauma. (See, for example, Beal, M. F., xe2x80x9cMechanisms of excitotoxicity in neurologic diseases,xe2x80x9d FASEB J., 6:3338-3344 (1992); and Choi, D. W., xe2x80x9cExcitotoxic cell death,xe2x80x9d J. Neurobiol., 23:1261-1276 (1992).) Toxicity to the inner retina has been observed following intravitreal injection of EAAs following application of EAAs to the isolated animal retina or from exogenously applied glutamate to retinal ganglion cells in culture. See generally, Sattayasai, et al., xe2x80x9cMorphology of quisqualate-induced neurotoxicity in the chicken retina,xe2x80x9d Invest. Ophthalmol. Vis. Sci., 28:106-117 (1987); Tung et al., xe2x80x9cA quantitative analysis of the effects of excitatory neurotoxins on retinal ganglion cells in the chick, Visual Neurosci., 4:217-223 (1990); Sisk et al., xe2x80x9cHistological changes in the inner retina of albino rats following intravitreal injection of monosodium L-glutamate,xe2x80x9d Graefe""s Arch. Clin. Exp. Ophthalmol., 223:250-258 (1985); Siliprandi et al., xe2x80x9cN-methyl-D-aspartate-induced neurotoxicity in the adult rat retina,xe2x80x9d Visual Neurosci., 8:567-573 (1992); Reif-Lehrer et al., xe2x80x9cEffects of monosodium glutamate on chick embryo retina in culture,xe2x80x9d Invest. Ophthalmol. Vis. Sci., 14(2):114-124 (1975); Blanks, J. C., xe2x80x9cEffects of monosodium glutamate on the isolated retina of the chick embryo as a function of age: A morphological study,xe2x80x9d Exp. Eye Res., 32:105-124 (1981); Olney et al., xe2x80x9cThe role of specific ions in glutamate neurotoxicity,xe2x80x9d Neurosci. Lett., 65:65-71 (1986); Olney et al., xe2x80x9cThe anti-excitotoxic effects of certain anesthetics, analgesics and sedative-hypnotics,xe2x80x9d Neurosci. Lett 68:29-34 (1986); Price et al., xe2x80x9cCNQX potently and selectively blocks kainate excitotoxicity in the chick embryo retina,xe2x80x9d Soc. Neurosci. Abst., 14:418 (1988); David et al., xe2x80x9cInvolvement of excitatory neurotransmitters in the damage produced in chick embryo retinas by anoxia and extracellular high potassium,xe2x80x9d Exp. Eve Res., 46:657-662 (1988); Caprioli et al., xe2x80x9cLarge retinal ganglion cells are more susceptible to excitotoxic and hypoxic injury than small cells Invest. Ophthalmol. Vis. Sci., 34(Suppl):1429 (1993); Cummins et al., xe2x80x9cElectrophysiology of cultured retinal ganglion cells to investigate basic mechanics of damage,xe2x80x9d Glaucoma Update IV, 59-65 (1991); and Sucher et al., xe2x80x9cN-methyl-D-aspartate antagonists prevent kainate neurotoxicity in rat retinal ganglion cells in vitro,xe2x80x9d J. Neurosci., 11(4):966-971 (1991).
EAA receptors have been characterized as metabotropic or ionotropic. Activation of a metabotropic receptor affects cellular processes via G-proteins; whereas ionotropic receptors affect the translocation of mono- and divalent cations across the cell membrane. There are at least three ionotropic receptors that have been named for the agonist that preferentially stimulates the receptor. These receptors have been classified as: N-methyl-D-aspartate (NMDA); kainate; and AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propanoic acid). These EAA receptors are differentially distributed to specific cells in the retina. (See, for example, Massey, S., xe2x80x9cCell types using glutamate as a neurotransmitter in the vertebrate retina,xe2x80x9d N. N. Osborne and G. J. Chader (Eds.) Progress in Retinal Research, Ch. 9, Pergammon Press: Oxford, 399-425 (1990); and Miller et al., xe2x80x9cExcitatory amino acid receptors in the vertebrate retina,xe2x80x9d in Retinal Transmitters and Modulators: Models for the Brain, (W. W. Morgan, Ed.) CRC Press, Inc., Boca Raton, II:123-160 (1985).) The localization of such receptors would account for the pathologies associated with glaucoma or inner retinal ischemia. For example, death of the retinal ganglion cell has to a large part been attributed to the NMDA receptor. (See, for example, Sucher et al., xe2x80x9cN-methyl-D-aspartate antagonists prevent kainate neurotoxicity in retinal ganglion cells in vitro,xe2x80x9d J. Neurosci., 11(4):966-971 (1991).). Thus, antagonists of the NMDA receptor are neuroprotective; however, not all antagonists of the diversely distributed EAA receptors are neuroprotective to the inner retina through antagonism of the NMDA receptor, Zeevalk et al., xe2x80x9cAction of the anti-ischemic agent ifenprodil on N-methyl-D-aspartate and kainate-mediated excitotoxicity,xe2x80x9d Brain Res., 522:135-139 (1990)), and many of these EAA antagonists have significant CNS side-effects and are therefore not suitable for treating these degenerative diseases of the eye.
The present invention is directed to the use of a glutamate antagonist and an IOP controlling agent, dosed separately or in combination for the treatment of persons suffering from glaucoma or ocular hypertension.